Acute Reduction Research Articles

Impact of resistance training sets performed until muscular failure with different loads on intraocular pressure and ocular perfusion pressure.

The aim of this article is to investigate the acute effects of bench press sets leading to muscular failure with different loads on intraocular pressure and ocular perfusion pressure. A randomized experimental study. Seventeen physically active young men performed four resistance training sets of bench press to muscular failure against different relative loads (65% one-repetition maximum vs 75% one-repetition maximum vs 85% one-repetition maximum vs 95% one-repetition maximum). Intraocular pressure was measured before and immediately after the execution of each of the four sets, and ocular perfusion pressure was also assessed before and after physical effort. We found that intraocular pressure increased after reaching muscular failure (p < 0.001, ƞ²= 0.52), being also dependent on the interaction load × point of measure (p < 0.001, ƞ²= 0.33). Our data demonstrated that higher intraocular pressure increases were found when participants performed the bench press exercise against heavier loads, showing statistical significance for the 75% one-repetition maximum (p = 0.020, d = -0.63, mean change = 0.9 mmHg), 85% one-repetition maximum (p = 0.035, d = -0.56, mean change = 1.4 mmHg), and 95% one-repetition maximum (p < 0.001, d = -1.36, mean change = 2.9 mmHg) relative loads. For its part, ocular perfusion pressure showed a reduction after exercise (p = 0.009, ƞ²= 0.35), being these changes independent on the load used. Bench press exercise leading to muscular failure provokes an acute intraocular pressure rise, with greater changes when heavier loads are used. Ocular perfusion pressure exhibited an acute reduction after exercise; however, its clinical relevance seems to be insignificant (lower to 4%). We argue that the use of heavy loads, when training to muscular failure, should be discouraged in order to avoid acute intraocular pressure fluctuations. Future studies should corroborate the generalizability of these findings in glaucoma patients.

Occipital and Cerebellar Theta Burst Stimulation for Mal De Debarquement Syndrome.

Individuals with Mal de Debarquement syndrome (MdDS) experience persistent oscillating vertigo lasting for months or years. Transcranial magnetic stimulation (TMS) can modulate the motion perception of MdDS. Twenty-six TMS naive individuals received single administrations of continuous theta burst stimulation (cTBS) over the occipital cortex, cerebellar vermis, and lateral cerebellar hemisphere, in randomized order. A 0-100 point Visual Analogue Scale was used to assess acute changes in oscillating vertigo severity after each session. Repeated treatments were given over the target that led to the most acute reduction in symptoms. All treatments were performed with neuronavigation using the participant's own brain MRI. The Dizziness Handicap Inventory (DHI), MdDS Balance Rating Scale (MBRS), and Hospital Anxiety and Depression Scale (HADS) were assessed weekly at four pretreatment and six posttreatment time points. Twenty participants chose either the occipital cortex (11) or cerebellar vermis (9) targets as most effective in reducing the oscillating vertigo; one chose lateral cerebellar hemisphere; five chose none. After 10 to 12 sessions of 1,200 pulses over the target of choice, 19 of 25 treatment completers noted ≥ 25% reduction, 12 of 25 ≥50% reduction, and 8 of 25 ≥75% reduction in oscillating vertigo intensity. A one-way repeated measures ANOVA of DHI, MBRS, and HADS scores before and after treatment showed significant reductions in DHI, MBRS, and the HADS Anxiety subscore immediately after treatment with most improvement lasting through posttreatment week 6. There were no significant Depression subscore changes. Participants who had chosen vermis stimulation had comparatively worse balance at baseline than those who had chosen occipital cortex stimulation. cTBS over either the occipital cortex or cerebellar vermis is effective in reducing the oscillating vertigo of MdDS acutely and may confer long-term benefits. Sustained improvement requires more frequent treatments.

Individualizing Revascularization Strategy for Diabetic Patients With Multivessel Coronary Disease

BackgroundIn patients with diabetes and multivessel coronary artery disease (CAD), the FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial demonstrated that, on average, coronary artery bypass grafting (CABG) was superior to percutaneous coronary intervention (PCI) for major acute cardiovascular events (MACE) and angina reduction. Nonetheless, multivessel PCI remains a common revascularization strategy in the real world. ObjectivesTo translate the results of FREEDOM to individual patients in clinical practice, risk models of the heterogeneity of treatment benefit were built. MethodsUsing patient-level data from 1,900 FREEDOM patients, the authors developed models to predict 5-year MACE (all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke) and 1-year angina after CABG and PCI using baseline covariates and treatment interactions. Parsimonious models were created to support clinical use. The models were internally validated using bootstrap resampling, and the MACE model was externally validated in a large real-world registry. ResultsThe 5-year MACE occurred in 346 (18.2%) patients, and 310 (16.3%) had angina at 1 year. The MACE model included 8 variables and treatment interactions with smoking status (c = 0.67). External validation in stable CAD (c = 0.65) and ACS (c = 0.68) demonstrated comparable performance. The 6-variable angina model included a treatment interaction with SYNTAX score (c = 0.67). PCI was never superior to CABG, and CABG was superior to PCI for MACE in 54.5% of patients and in 100% of patients with history of smoking. ConclusionsTo help disseminate the results of FREEDOM, the authors created a personalized risk prediction tool for patients with diabetes and multivessel CAD that could be used in shared decision-making for CABG versus PCI by estimating each patient’s personal outcomes with both treatments.

Influence of acute reduction of blood viscosity on endothelial function.

The relationship between blood viscosity (BV) and endothelial function is rather complex. An increase in BV causes an increase in blood flow resistance, with negative hemodynamic effects; on the other hand, a moderate increase in BV causes an increase in wall stress shear (WSS), and consequent beneficial effects. As a matter of fact, the effect of changes in BV on endothelial function is not yet clear. Aim of the present study was to evaluate in-vivo the effects of the acute reduction in BV on endothelial function, in healthy male subjects. Fourteen healthy male blood donors were studied before and 48 hours after blood donation. Blood and plasma viscosity were measured at 37C° with a cone-plate viscometer. Endothelial function was evaluated through flow mediated vasodilation (FMD). Blood viscosity was reduced after blood donation (BV225 (cP) 4.53±0.59 vs.4.18±0.31, p < 0.05). FMD 50 s after cuff deflation was unchanged: 6.23±3.84 vs. 6.62±4.81, p = NS. The vasodilation, however, lasted longer and the area under the curve of FMD was significantly increased: 8.74±8.77 vs.16.14±8.65, p < 0.005. The present results demonstrate that the acute reduction of BV prolongs vasodilation, without affecting the amount of vasodilatation, possibly as adaptive reaction allowing more time for oxygen release.

Risk Categorization Using New American College of Cardiology/American Heart Association Guidelines for Cholesterol Management and Its Relation to Alirocumab Treatment Following Acute Coronary Syndromes.

The 2018 US cholesterol management guidelines recommend additional lipid-lowering therapies for secondary prevention in patients with low-density lipoprotein cholesterol ≥70 mg/dL or non-high-density lipoprotein cholesterol ≥100 mg/dL despite maximum tolerated statin therapy. Such patients are considered at very high risk (VHR) based on a history of >1 major atherosclerotic cardiovascular disease (ASCVD) event or a single ASCVD event and multiple high-risk conditions. We investigated the association of US guideline-defined risk categories with the occurrence of ischemic events after acute coronary syndrome and reduction of those events by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor. In the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), patients with recent acute coronary syndrome and residual dyslipidemia despite optimal statin therapy were randomly assigned to alirocumab or placebo. The primary trial outcome (major adverse cardiovascular events, ie, coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) was examined according to American College of Cardiology/American Heart Association risk category. Of 18 924 participants followed for a median of 2.8 years, 11 935 (63.1%) were classified as VHR: 4450 (37.3%) had multiple prior ASCVD events and 7485 (62.7%) had 1 major ASCVD event and multiple high-risk conditions. Major adverse cardiovascular events occurred in 14.4% of placebo-treated patients at VHR versus 5.6% of those not at VHR. In the VHR category, major adverse cardiovascular events occurred in 20.4% with multiple prior ASCVD events versus 10.7% with 1 ASCVD event and multiple high-risk conditions. Alirocumab was associated with consistent relative risk reductions in both risk categories (hazard ratio=0.84 for VHR; hazard ratio=0.86 for not VHR; Pinteraction=0.820) and by stratification within the VHR group (hazard ratio=0.86 for multiple prior ASCVD events; hazard ratio=0.82 for 1 major ASCVD event and multiple high-risk conditions; Pinteraction=0.672). The absolute risk reduction for major adverse cardiovascular events with alirocumab was numerically greater (but not statistically different) in the VHR group versus those not at VHR (2.1% versus 0.8%; Pinteraction=0.095) and among patients at VHR with multiple prior ASCVD events versus a single prior ASCVD event (2.4% versus 1.8%; Pinteraction=0.661). The US guideline criteria identify patients with recent acute coronary syndrome and dyslipidemia who are at VHR for recurrent ischemic events and who may derive a larger absolute benefit from treatment with alirocumab. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402.

Estimation oxidant and Anti oxidant of patients with changeful heart discomfort and myocardiac breach of Diwaniya-Iraq

The present study aimed check the relation amidst level oxidate and Anti oxidants of person at changeful heart discomfort (type of heart disease), myocardiac breach while identify role oxidate in develop disease of individual province of diwaniya-iraq. the study of patients who are divided into three category (A) included 45 patients changeful heart discomfort pectoris in different age, category (B) included 45 patients with acute myocardiac breach at different age and category 45 (C) as control. The results demonstrate show a significant decrease (p⩾ 0.05) in vitamin E, C, glutathion peroxidas and Glutathione ( GSH ) but the reverse was significant increase (p⩽ 0.05) caeruloplasmin (ferroxidase enzyme), and Malondialdehyde( MDA) of individual changeful heart discomfor pectoris and myocardiac breach. The conclusion of study the negative role of high free radical was subsisted heart esdisorder progress. The acute myocardiac breach work reduction of O2 surrender to myocardiaic lead produce of interactive O2 groupe that effective role in the development and generate heart desorder.

Acute inhibition of protein deacetylases does not impact skeletal muscle insulin action.

Whether the histone deacetylase (HDAC) and sirtuin families of protein deacetylases regulate insulin-stimulated glucose uptake, independent of their transcriptional effects, has not been studied. Our objective was to determine the nontranscriptional role of HDACs and sirtuins in regulation of skeletal muscle insulin action. Basal and insulin-stimulated glucose uptake and signaling and acetylation were assessed in L6 myotubes and skeletal muscle from C57BL/6J mice that were treated acutely (1 h) with HDAC (trichostatin A, panobinostat, TMP195) and sirtuin inhibitors (nicotinamide). Treatment of L6 myotubes with HDAC inhibitors or skeletal muscle with a combination of HDAC and sirtuin inhibitors increased tubulin and pan-protein acetylation, demonstrating effective impairment of HDAC and sirtuin deacetylase activities. Despite this, neither basal nor insulin-stimulated glucose uptake or insulin signaling was impacted. Acute reduction of the deacetylase activity of HDACs and/or sirtuins does not impact insulin action in skeletal muscle.

Postprandial activation of leukocyte-endothelium interaction by fatty acids in the visceral adipose tissue microcirculation.

High-fat diet (HFD)-induced obesity is associated with accumulation of inflammatory cells predominantly in visceral adipose depots [visceral adipose tissue (VAT)] rather than in subcutaneous ones [subcutaneous adipose tissue (SAT)]. The cellular and molecular mechanisms responsible for this phenotypic difference remain poorly understood. Controversy also exists on the overall impact that adipose tissue inflammation has on metabolic health in diet-induced obesity. The endothelium of the microcirculation regulates both the transport of lipids and the trafficking of leukocytes into organ tissue. We hypothesized that the VAT and SAT microcirculations respond differently to postprandial processing of dietary fat. We also tested whether inhibition of endothelial postprandial responses to high-fat meals (HFMs) preserves metabolic health in chronic obesity. We demonstrate that administration of a single HFM or ad libitum access to a HFD for 24 h quickly induces a transient P-selectin-dependent inflammatory phenotype in the VAT but not the SAT microcirculation of lean wild-type mice. Studies in P-selectin-deficient mice confirmed a mechanistic role for P-selectin in the initiation of leukocyte trafficking, myeloperoxidase accumulation, and acute reduction in adiponectin mRNA expression by HFMs. Despite reduced VAT inflammation in response to HFMs, P-selectin-deficient mice still developed glucose intolerance and insulin resistance when chronically fed an HFD. Our data uncover a novel nutrient-sensing role of the vascular endothelium that instigates postprandial VAT inflammation. They also demonstrate that inhibition of this transient postprandial inflammatory response fails to correct metabolic dysfunction in diet-induced obesity.-Preston, K. J., Rom, I., Vrakas, C., Landesberg, G., Etwebe, Z., Muraoka, S., Autieri, M., Eguchi, S., Scalia, R. Postprandial activation of leukocyte-endothelium interaction by fatty acids in the visceral adipose tissue microcirculation.

Acute antihypertensive effect of self-selected exercise intensity in older women with hypertension: a crossover trial.

PurposeAcute reduction in blood pressure (BP) following an exercise session is evidenced in controlled settings with formal supervision in hypertensive older populations. This study investigated the effect of a self-selected exercise (SSE)-intensity session on ambulatory BP in hypertensive older women in a “real-world” setting.MethodsTwenty inactive older women with hypertension (64.9±4.5 years) were included in this randomized, controlled, crossover trial. After baseline assessments, participants performed 30 minutes of an SSE-intensity session on an outdoor track and a control session, separated by 7-10 days. Heart rate (HR), rating of perceived exertion (RPE), and affective response were assessed. Ambulatory BP was monitored for 20 hours following both sessions. Paired t-tests and generalized estimation were used for data analysis.ResultsParticipants exercised at 5.1±1.1 km/h, spent ~90% of the exercise time at moderate–vigorous intensity (≥40% of heart rate reserve). SSE-intensity session was reported as light (RPE 11.0±1.5) and pleasant (affect 3.4±1.2). SSE-intensity session elicited reductions in systolic BP in the first 6 hours postexercise (6.0 mmHg, CI 2.7–9.3 mmHg; P<0.001). Average systolic BP in the 20-hour (−3.4 mmHg, CI −5.9 to −0.9 mmHg; P=0.010) and awake (−4.0 mmHg, CI −6.4 to −1.6 mmHg; P=0.003) periods were lower following SSE-intensity session compared to control session. No differences were observed in average systolic BP during asleep period and diastolic BP during the 20-hour awake and asleep periods between the SSE-intensity session and control session (P>0.05).ConclusionAn SSE-intensity session elicited a reduction in ambulatory systolic BP in inactive older women with hypertension during awake and 20-hour periods. Also, the SSE-intensity session was reported as light and pleasant.

Temporal plasticity of insulin and incretin secretion and insulin sensitivity following sleeve gastrectomy contribute to sustained improvements in glucose control

ObjectiveBariatric surgery acutely improves glucose control, an effect that is generally sustained for years in most patients. The acute postoperative glycemic reduction is at least partially mediated by enhanced incretin secretion and islet function, and occurs independent of caloric restriction, whereas the sustained improvement in glucose control is associated with increased insulin sensitivity. However, studies in humans with bariatric surgery suggest that these elevations are not static but undergo coordinated regulation throughout the postoperative time course. The studies described here test the hypothesis that incretin secretion, islet function, and peripheral insulin sensitivity undergo temporal regulation following bariatric surgery as a means to regulate glucose homeostasis. MethodsIncretin secretion, islet function, and insulin sensitivity in mice with vertical sleeve gastrectomy (VSG) were compared to sham-operated controls that were pair-fed for 90d, matching food consumption and body-weight between groups. ResultsGlucose clearance and insulin secretion were enhanced in VSG mice compared to controls during mixed-meal tolerance tests (MMTT) at 12 and 80 days postoperatively, as were prandial GLP-1, GIP, and glucagon levels. Insulin sensitivity was comparable between groups 14d after surgery, but significantly greater in the VSG group at day 75, despite similar body-weight gain between groups. Glucose stimulated insulin secretion was greater in VSG mice compared to controls in vivo (I.P. glucose injection) and ex vivo (islet perifusion) indicating a rapid and sustained enhancement of β-cell function after surgery. Notably, glycemia following a MMTT was progressively higher over time in the control animals but improved in the VSG mice at 80d despite weight regain. However, meal-stimulated incretin secretion decreased in VSG mice from 10 to 80 days postoperative, as did meal-stimulated and I.P. glucose-stimulated insulin secretion. This occurred over the same time period that insulin sensitivity was enhanced in VSG mice, suggesting postoperative islet output is tightly regulated by insulin demand. ConclusionsThese data demonstrate a dynamic, multifactorial physiology for improved glucose control after VSG, whereby rapidly elevated insulin secretion is complimented by later enhancements in insulin sensitivity. Critically, the glucose lowering effect of VSG is demonstrably larger than that of caloric-restriction, suggesting these adaptations are mediated by surgical modification of gastrointestinal anatomy and not weight-loss per se.

MON-300 EFFICACY AND SAFETY OF CANAGLIFLOZIN, A SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR, IN DIABETIC KIDNEY DISEASE: A RANDOMIZED OPEN-LABEL PROSPECTIVE TRIAL

Sodium glucose cotransporter 2 (SGLT2) inhibitors are expected to have, renoprotective effects based on the possible mechanism that SGLT2 inhibitors reduce hyperfiltration by blocking proximal tubule sodium reabsorption and activating tubuloglomerular feedback (TGF) and may decrease inflammatory, fibrotic, and hyperplastic response of proximal tubular cells by blocking glucose reabsorption into proximal tubular cells. Although SGLT2 inhibition is associated with an acute reduction in estimated glomerular filtration rate (eGFR) by about 4-6 mL/min per 1.73m2, eGFR typically has a tendency to return to baseline and remains stable thereafter. Furthermore, a 30 to 40% reduction in albuminuria was found. However, the effects of SGLT2 inhibition are unclear with regard to other kidney related biomarkers, such as those associated with tubulointerstitial damage. In the present study, we aimed to examine precisely the renoprotective effects of the SGLT2 inhibitor canagliflozin by measuring albuminuria, tubulointerstitial biomarkers, eGFR, and other metabolic parameters in patients with diabetic kidney disease (DKD) who are treated with renin-angiotensin system (RAS) inhibitors. In this prospective, open-label, parallel-group study, Japanese diabetes patients were randomized to receive either oral canagliflozin (100 mg/day) or usual care (control group) for 52 weeks. Before randomization, patients received fixed doses of conventional antidiabetic drugs (oral drugs and/or insulin) and RAS inhibitors for 8 weeks; these drugs were continued during the study. A total of 44 patients were randomly assigned to the canagliflozin group (n = 22) or the control group (n = 22). Endpoints included changes in urinary albumin-to-creatinine ratio (UACR), other urinary biomarkers, laboratory and vital parameters, and adverse events. Both groups included 22 patients in the analysis. Mean change in UACR was -221 g/gCr and 81 mg/gCr in the canagliflozin and control groups, respectively (P=0.004). Percent reduction in UACR was significantly greater in the canagliflozin group than in the control group (-49 ± 26% vs. 24 ± 47 %; P<0.0001). Urinary liver-type fatty acid binding protein (L-FABP), N-acetyl-β-D-glucosaminidase (NAG), and β2-microglobulin levels were also significantly decreased in the canagliflozin group, but not in the control group. Mean change in eGFR at the end of the study was 0.7 and -3.4 mL/min/1.73m2 in the canagliflozin and control group, respectively (P=0.024). A significant decrease in body mass index (BMI), systolic, diastolic blood pressure (BP), and mean arterial pressure was observed in the canagliflozin group. In addition, canagliflozin was associated with a significant increase in hemoglobin concentrations and hematocrit levels. Canagliflozin treatment leads to a reduction in albuminuria, urinary L-FABP, NAG, and β2-microglobulin levels in patients with DKD, regardless of simultaneous RAS inhibition. Furthermore, after 52 weeks, canagliflozin, in contrast to the control treatment, significantly reduced HbA1c and was associated with reductions in body weight, BPs, and liver transaminase levels in patients with DKD. The effect of canagliflozin on UACR appeared to be, in large part, beyond the effects on glycemic control. These findings suggest that canagliflozin may be an appropriate treatment option for patients with DKD.

MON-302 ADMINISTRATION OF DAPAGLIFLOZIN IN TYPE 2 DIABETES MELLITUS PATIENTS WITH CHRONIC KIDNEY DISEASE: A SYSTEMATIC REVIEW

The increasing number of diabetes mellitus has led to an increase in the incidence of chronic kidney disease (CKD). Roughly, a third of all patients with diabetes mellitus also develop CKD as the disease progresses. Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, is the latest agent used in type 2 diabetes mellitus patients. The drug lower blood sugar levels by prevent glucose reabsorption in the proximal renal tubule. Inhibition of sodium reabsorption, on the other hand, manifested as an acute reduction in glomerular filtration rate (GFR) and albuminuria. This systematic review aims to analyze the clinical impact of dapagliflozin uses in type 2 diabetes patients with CKD. Interventional studies related to dapaglifozin administration in type 2 diabetes mellitus patients with chronic kidney disease were reviewed systematically. Inaugural literature searching was finished in four scientific databases (PubMed, EbscoHost, ProQuest, and Cochrane) using specific medical subheading (MeSH) terms and filters. Articles screened and selected by three authors independently to prevent bias. Studies that were relevant included to be further reviewed using tools provided by Centre for Evidence-based Medicine (CEBM). Two related articles were included in the review. Dapagliflozin was administered in a total of 441 type 2 diabetes mellitus patients with stages 3a-4 CKD. Study period ranged between 24-weeks to 104-weeks. Investigation reveals dapagliflozin considered as safe and effective in moderate renal impairment. However, the capacity of the drug to lower blood glucose levels tend to decrease in severe impaired renal function. This review draws to the conclusion that dapagliflozin administration may not improve glycemic index in diabetes mellitus patients with severe chronic kidney disease.

Repetitive transcranial magnetic stimulation recovers cortical map plasticity induced by sensory deprivation due to deafferentiation.

Key points Partial sensory deprivation (deafferentation) by removing whiskers from the rat snout resulted in a reduced responsiveness of related cortical representations.Repetitive transcranial magnetic stimulation (three blocks of intermittent theta‐burst) applied for 5 days in combination with sensory exploration restored the normal responsiveness level of the deafferented barrel cortex.However, intracortical inhibition (lateral and recurrent) appeared to be reduced after repetitive transcranial magnetic stimulation, probably as the cause of improved responsiveness.Repetitive transcranial magnetic stimulation also reduced the asymmetry of the lateral spread of sensory activity. Repetitive transcranial magnetic stimulation (rTMS) modulates human cortical excitability. It has the potential to support recovery to normal cortical function when the excitation–inhibition balance is altered (e.g. after a stroke or loss of sensory input). We tested cortical map plasticity on the basis of sensory responses (local field potentials, LFPs) and expression of neuronal activity marker proteins within the barrel cortex of rats receiving either active or sham rTMS after selective unilateral deafferentation by whiskers plucking. Rats received daily rTMS [intermittent theta‐burst (iTBS), active or sham] for 5 days before exploring an enriched environment. Our previous studies indicated a disinhibitory effect of iTBS on cortical activity. Therefore, we also expected disinhibitory effects if deafferentation causes depression of sensory responses. Deafferentation resulted in an acute general reduction of sensory responsiveness and enhanced expression of inhibitory activity markers (GAD67, parvalbumin) in the deafferented hemisphere. Active but not sham‐iTBS‐rTMS normalized these measures. The stronger caudal‐to‐frontal horizontal spread of activity across barrels was reduced after deafferentation but not restored after active iTBS, despite generally increased responses. Fitting the LFP data with a computational model of different strengths and types of excitatory and inhibitory connections further revealed an iTBS‐induced reduction of lateral and recurrent inhibition as the most probable scenario. Whether the disinhibitory effect of iTBS for the restoration of normal cortical function in the acute phase of depression after deafferentiation is also beneficial in humans remains to be demonstrated. As recently discussed, disinhibition appears to be required to open a window for neuronal plasticity.

Nociceptive pulmonary-cardiac reflexes are altered in the spontaneously hypertensive rat.

We investigated the cardiovascular and respiratory responses of the normotensive Wistar-Kyoto (WKY) rat and the spontaneously hypertensive (SH) rat to inhalation and intravenous injection of the noxious stimuli allyl isothiocyanate (AITC). AITC inhalation evoked atropine-sensitive bradycardia in conscious WKY rats, and evoked atropine-sensitive bradycardia and atenolol-sensitive tachycardia with premature ventricular contractions (PVCs) in conscious SH rats. Intravenous injection of AITC evoked bradycardia but no tachycardia/PVCs in conscious SHs, while inhalation and injection of AITC caused similar bradypnoea in conscious SH and WKY rats. Anaesthesia (inhaled isoflurane) inhibited the cardiac reflexes evoked by inhaled AITC but not injected AITC. Data indicate the presence of a de novo nociceptive pulmonary-cardiac reflex triggering sympathoexcitation in SH rats, and this reflex is dependent on vagal afferents but is not due to steady state blood pressure or due to remodelling of vagal efferent function. Inhalation of noxious irritants/pollutants activates airway nociceptive afferents resulting in reflex bradycardia in healthy animals. Nevertheless, noxious pollutants evoke sympathoexcitation (tachycardia, hypertension) in cardiovascular disease patients. We hypothesize that cardiovascular disease alters nociceptive pulmonary-cardiac reflexes. Here, we studied reflex responses to irritants in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive (SH) rats. Inhaled allyl isothiocyanate (AITC) evoked atropine-sensitive bradycardia with atrial-ventricular (AV) block in conscious WKY rats, thus indicating a parasympathetic reflex. Conversely, inhaled AITC in conscious SH rats evoked complex brady-tachycardia with both AV block and premature ventricular contractions (PVCs). Atropine abolished the bradycardia and AV block, but the atropine-insensitive tachycardia and PVCs were abolished by the β1 -adrenoceptor antagonist atenolol. The aberrant AITC-evoked reflex in SH rats was not reduced by acute blood pressure reduction by captopril. Surprisingly, intravenous AITC only evoked bradycardia in conscious SH and WKY rats. Furthermore, anaesthesia reduced the cardiac reflexes evoked by inhaled but not injected AITC. Nevertheless, anaesthesia had little effect on AITC-evoked respiratory reflexes. Such data suggest distinct differences in nociceptive reflex pathways dependent on cardiovascular disease, administration route and downstream effector. AITC-evoked tachycardia in decerebrate SH rats was abolished by vagotomy. Finally, there was no difference in the cardiac responses of WKY and SH rats to vagal efferent electrical stimulation. Our data suggest that AITC inhalation in SH rats evokes de novo adrenergic reflexes following vagal afferent activation. This aberrant reflex is independent of steady state hypertension and is not evoked by intravenous AITC. We conclude that pre-existing hypertension aberrantly shifts nociceptive pulmonary-cardiac reflexes towards sympathoexcitation.

P2X1 receptor blockers reduce the number of circulating thrombocytes and the overall survival of urosepsis with haemolysin-producing Escherichia coli.

Urosepsis is a severe condition often caused by Escherichia coli that spontaneously have ascended the urinary tract to the kidneys causing pyelonephritis and potentially bacteraemia. The number of sepsis cases has been steadily increasing over the last decades, and there are still no specific, molecular supportive therapies for sepsis to supplement antibiotic treatment. P2X1 receptors are expressed by a number of immune cells including thrombocytes, which presently have been established as an important player in the acute immune response to bacterial infections. P2X1 receptor-deficient mice have been shown to be relatively protected against urosepsis, with markedly reduced levels of circulating proinflammatory cytokines and intravascular coagulation. However, here we show that continuous intravenous infusion with P2X1 receptor antagonist markedly accelerates development of a septic response to induced bacteraemia with uropathogenic E. coli. Mice exposed to the P2X1 receptor antagonists die very early with haematuria, substantially elevated plasma levels of proinflammatory cytokines, massive intravascular coagulation and a concomitant reduction in circulating thrombocytes. Interestingly, infusion of P2X1 receptor antagonists causes a marked acute reduction in circulating thrombocytes and a higher number of bacteria in the blood. These data support the notion that the number of functional thrombocytes is important for the acute defence against bacteria in the circulation and that the P2X1 receptor potentially could be essential for this response.

Revascularisation and mechanical circulatory support in patients with ischaemic cardiogenic shock

### Learning objectives Cardiogenic shock (CGS) complicates 5 – 10% of cases of acute myocardial infarction (AMI) and the most common cause of CGS is AMI (80% of cases).1 When...

Management of hyperkalemia in patients with kidney disease: a position paper endorsed by the Italian Society of Nephrology

Hyperkalemia (HK) is the most common electrolyte disturbance observed in patients with kidney disease, particularly in those in whom diabetes and heart failure are present or are on treatment with renin–angiotensin–aldosterone system inhibitors (RAASIs). HK is recognised as a major risk of potentially life threatening cardiac arrhythmic complications. When an acute reduction of renal function manifests, both in patients with chronic kidney disease (CKD) and in those with previously normal renal function, HK is the main indication for the execution of urgent medical treatment and the recourse to extracorporeal replacement therapies. In patients with end-stage renal disease, the presence of HK not responsive to medical therapy is an indication at the beginning of chronic renal replacement therapy. HK can also be associated indirectly with the progression of CKD, because the finding of high potassium values leads to withdrawal of treatment with RAASIs, which constitute the first choice nephro-protective treatment. It is therefore essential to identify patients at risk of developing HK, and to implement therapeutic interventions aimed at preventing and treating this dangerous complication of kidney disease. Current strategies aimed at the prevention and treatment of HK are still unsatisfactory, as evidenced by the relatively high prevalence of HK also in patients under stable nephrology care, and even in the ideal setting of randomized clinical trials where optimal treatment and monitoring are mandatory. This position paper will review the main therapeutic interventions to be implemented for the prevention, detection and treatment of HK in patients with CKD on conservative care, in those on dialysis, in patients in whom renal disease is associated with diabetes, heart failure, resistant hypertension and who are on treatment with RAASIs, and finally in those presenting with severe acute HK.

Stretch-shortening cycle exercise produces acute and prolonged impairments on endurance performance: is the peripheral fatigue a single answer?

This study aimed to verify the acute and prolonged effects of stretch-shortening cycle exercise (SSC) on performance and neuromuscular function following a 4-km cycling time trial (4-km TT). On separate days, individuals performed a 4-km TT without any previous exercise (CON), immediately (ACUTE) and 48h after (PROL) SSC protocol (i.e., 100-drop jumps). Neuromuscular function was measured at baseline SSC (baseline), before (pre-TT) and after (post-TT) 4-km TT. Muscle soreness and inflammatory responses also were assessed. The endurance performance was impaired in both ACUTE (- 2.3 ± 1.8%) and PROL (- 1.8 ± 2.4%) compared with CON. The SSC protocol caused also an acute reduction in neuromuscular function, with a greater decrease in potentiated quadriceps twitch-force (Qtw.pot - 49 ± 16%) and voluntary activation (VA - 6.5 ± 7%) compared for CON and PROL at pre-TT. The neuromuscular function was fully recovered 48h after SSC protocol. Muscle soreness and IL-10 were elevated only 48h after SSC protocol. At post-TT, Qtw.pot remained lower in ACUTE (- 52 ± 14%) compared to CON (- 29 ± 7%) and PROL (- 31 ± 16%). These findings demonstrate that impairment in endurance performance induced by prior SSC protocol was mediated by two distinct mechanisms, where the acute impairment was related to an exacerbated degree of peripheral and central fatigue, and the prolonged impairment was due to elevated perceived muscle soreness.

Furin Inhibition as a Mechanism to Reduce Aberrant ENaC‐Mediated Sodium Transport and Rehydrate the Airways in Cystic Fibrosis Lung Disease

The epithelial sodium channel (ENaC) is found in a number of tissues including lung epithelia and is activated through proteolytic cleavage of its α and γ subunits. Dysregulation of ENaC, secondary to the loss of functional CFTR in cystic fibrosis (CF), leads to increased Na+ absorption which contributes to airways dehydration, thickened mucus and impaired mucociliary clearance (MCC). Pro‐protein convertases such as furin are implicated in the activation of a distinct pool of ENaC as it passes through the biosynthetic pathway (1). Furin cleaves α‐ENaC at two sites releasing a small inhibitory peptide from the extracellular loop, partially activating the channel, and subsequently cleaves γ‐ENaC. These actions ‘prime’ the channel for cleavage at a secondary site on the γ subunit by cell‐surface channel activating proteases such as prostasin, trypsin and neutrophil elastase (2–4). Furin, therefore plays a key role in the proteolytic regulation of ENaC‐mediated sodium absorption and presents a promising therapeutic target for CF lung disease.The aim of this first‐in‐kind study was to determine the effect of two chemically different, highly selective furin inhibitors (BOS‐981 and BOS‐318) on ENaC signaling and airway surface liquid (ASL) height, using primary human CF bronchial epithelial cells (HBEs).Fully differentiated HBEs homozygous for F508‐del, grown at air‐liquid interface, were used to determine ENaC activity via equivalent current (Ieq) readings obtained using a 24‐well Transepithelial Current Clamp (TECC‐24) system. ASL height was measured using confocal microscopy.We report BOS‐981 and BOS‐318 to be potent inhibitors of furin. Both compounds, applied basolaterally, significantly reduced ENaC‐mediated Na+ absorption as measured by an acute reduction in amiloride‐sensitive Ieq after immediate treatment, which was sustained after longer (48 hr) exposure. The compounds also protected ENaC against cell surface activation by neutrophil elastase and CF sputum supernatant. Furthermore, the reduction in ENaC activity after a 48 hr treatment correlated with an increase in ASL height.These ground‐breaking results demonstrate that highly selective inhibition of furin by the novel inhibitors BOS‐981 and BOS‐318 presents a promising mechanism for the reduction of aberrant ENaC‐mediated Na+ absorption. This strategy has the potential to rehydrate the airways, restore effective MCC and reduce the devastating pulmonary decline observed in CF.Support or Funding InformationThis work was supported by funding from the MRC Proximity to Discovery: Industry Engagement FundThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Methicillin‐resistant Staphylococcus aureus causes sustained collecting lymphatic vessel dysfunction

Methicillin‐resistant Staphylococcus aureus (MRSA) is a major cause of morbidity and mortality worldwide and is a frequent cause of skin and soft tissue infections (SSTIs). Lymphedema—fluid accumulation in tissue caused by impaired lymphatic vessel function—is a strong risk factor for SSTIs. SSTIs also frequently recur in patients and sometimes lead to acquired lymphedema. However, the mechanism of how SSTIs can be both the consequence and the cause of lymphatic vessel dysfunction is not known.Here, we used the endemic USA300 strain of community‐associated MRSA (CA‐MRSA), a common cause of serious bacterial infections in the United States, to establish a model of localized MRSA infection. We used intravital imaging to determine whether MRSA infections inhibit lymphatic vessel contractility and lymph flow. In vivo studies used C57BL/6, iNOS−/− C57BL/6, MyD88−/− C57BL/6, LysMgfp/gfp C57BL/6, and alpha SMAP‐DsRed/C57BL/6 mice to assess the effects of host‐derived molecules to lymphatic contractility after infection. Alpha SMA‐DsRed transgenic mice were visualized and immunofluorescence staining of alpha SMA+ lymphatic muscle cells (LMCs) of WT mice was performed to analyze LMC coverage of lymphatic vessels on multiple days after infection. To define the molecular mechanisms related to this response, we performed cell viability and cell lysis assays and measured killing of LMCs by MRSA‐conditioned supernatant from wild type and mutant MRSA strain(s). Similar experiments were performed using recombinant MRSA toxins.Intravital imaging in mice revealed an acute reduction in both lymphatic vessel contractility and lymph flow after localized MRSA infection. Moreover, chronic lymphatic impairment is observed long after MRSA is cleared and inflammation is resolved. Associated with decreased collecting lymphatic vessel function was the loss and disorganization of lymphatic muscle cells (LMCs), which are critical for lymphatic contraction. In vitro, incubation with MRSA‐conditioned supernatant led to LMC death. Proteomic analysis identified several accessory gene regulator (agr)–controlled MRSA exotoxins that contribute to LMC death. Infection with agr mutant MRSA resulted in sustained lymphatic function compared to animals infected with wild‐type MRSA.Our findings suggest that agr is a promising target to preserve lymphatic vessel function and promote immunity during SSTIs.Support or Funding InformationThis work was supported by the National Institutes of Health under award numbers R21AI097745, DP2OD008780, R01CA214913, and R01HL128168 to Timothy Padera. Dennis Jones was supported in part by the UNCF‐Merck Science Initiative Postdoctoral Fellowship, Burroughs Wellcome Fund Postdoctoral Enrichment Program Award, and NIH NCI F32CA183465.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.